Microglia, the only immune cell found in the brain, account for 10% of the brain and are revealed to have essential functions to maintain the homeostasis in the brain such as phagocytic removal of wastes and repair of damaged tissues in the brain. Microglia contribute to maintain, enhance and improve the cognitive functions by maintaining the homeostasis in the brain. However, it is known that the excessive activation of microglia induces inflammation, and thus reactive oxygen species (ROS) and proinflammatory cytokines such as TNF-α and IL-β are chronically produced, thereby causing stress to neurons.
For example, even in patients with a mood disorder such as depression, chronic inflammation is caused and continuous production enhancement of proinflammatory cytokines and reactive oxygen species is recognized. Patients with a mood disorder have elevated blood CRP and proinflammatory cytokines values, and the correlation between these values and symptoms and treatment resistance is recognized. It is also reported that these marker values are normalized after disappearance of symptoms. Proinflammatory cytokines such as INF-γ and TNF-α and reactive oxygen species themselves have tissue disordering properties to nerve cells, neural stem cells and oligodendrocytes. In the brain of mood disorder patients, histological changes such as synaptic pathological changes, neurogenesis suppression, white matter changes are found and the proinflammatory cytokines and reactive oxygen species produced by microglia may be causing these changes (Non Patent Literature 1).
The reactive oxygen species and proinflammatory cytokines such as TNF-α produced by excessively activated microglia are reported to have been closely associated with pains and pathological conditions of chronic fatigue syndrome in addition to mood disorders including depression (Non Patent Literatures 2 to 7). Considering these findings, it is conceived that the suppression of the excessive microglia activation is useful to treat, relieve and further prevent diseases recognized to have been correlated with the excessive microglia activation such as pains, chronic fatigue syndrome, cognitive impairment and multiple sclerosis in addition to depression.
Some peptides have been disclosed as substances effective in suppressing microglial-mediated inflammation or to protect nerves. Patent Literature 1 discloses a peptide that suppresses microglial-mediated inflammation and protects nerves. A polypeptide including in the sequence the peptide consisting of 5 amino acids having a specific characteristic is disclosed as having actions to suppress the activation of microglia and suppress the inflammation. It is also suggested that the above peptide may be effective to various diseases including acute diseases and chronic diseases considered to have been related to microglial-mediated inflammation. Patent Literature 1 further describes the administration by injection or inhalation as the peptide administration method.
Patent Literature 2 discloses that nerves are continuously protected by intravenously administering tripeptide Gly-Pro-Glu (GPE) by an injection. The tripeptide administration particularly targets diseases accompanied by morphologically notable damages such as acute ischemic damage. In addition, it is not disclosed that the target is microglia.